Rho family GTPases are molecular switches that control signaling pathways regulating cytoskeleton reorganization, gene expression, cell cycle progression, cell survival, and other cellular processes (Etienne-Manneville, 2002), which is incorporated herein by reference in its entirety.
Rho family proteins constitute one of three major branches of the Ras superfamily. Rho proteins share approximately 30 percent amino acid identity with the Ras proteins. At least 14 mammalian Rho family proteins have been identified thus far, including RhoA, RhoB, RhoC, RhoD, RhoE/Rnd3, Rnd1/Rho6, Rnd2/Rho7, RhoG, Rac1, Rac2, Rac3, Cdc42, TC10, and TTF.
The various mature blood cell types are all ultimately derived from a single class of progenitor cell known as hematopoietic stem cells (HSCs). True stem cells are both pluripotent—that is they can give rise to all cell types—and capable of self-renewal. This is defined by their ability to repopulate an individual whose hematopoietic system has been destroyed by radiation or chemotherapy. Stem cells represent a very small percentage of bone marrow cells, and are normally quiescent. When stimulated to divide, they give rise to more committed, differentiated daughter cells with less proliferative potential, called “early progenitor” cells. Sequential rounds of division and differentiation give rise to an enormous amplification of cell numbers, necessary for the production of mature blood cells. This process of division and differentiation is subject to regulation at many levels to control cell production.
Leukocytic, hematopoietic cells are important in maintaining the body's defense against disease. For example, macrophages and lymphocytes are involved in potentiating the body's response to infection and tumors; granulocytes (neutrophils, eosinophils and basophils) are involved in overcoming infection, parasites and tumors. Other cell types derived from hematopoietic stem cells include platelets and erythrocytes.
Treatment of various cancers increasingly involves cytoreductive therapy, including high dose chemotherapy or radiation therapy. These therapies decrease a patient's white blood cell counts, suppress bone marrow hematopoietic activity, and increase the patient's risk of infection and/or hemorrhage. Depending on the degree of bone marrow damage (i.e., suppression), patients who undergo cytoreductive therapy must also receive therapy to reconstitute bone marrow function (hematopoiesis). Current treatments to manage the problems that result from prolonged bone marrow suppression include the reinfusion of a patient's own previously harvested hematopoietic stem and progenitor cells. In such procedures, patients undergo successive treatments with cell mobilization agents to cause mobilization of hematopoietic progenitor cells from the bone marrow to the peripheral circulation for harvesting. After harvesting, the patient is given high dose chemotherapy or radiotherapy and the bone marrow function is reconstituted by infusion of the cells harvested earlier.
The use of high-dosage chemotherapy or radiotherapy for bone marrow ablation requires subsequent incorporation of hematopoietic stem cells into the patient, in which case prior harvesting of such cells is required. The success of treatment crucially depends on the mobilization of the bone marrow stem cells, the subsequent return of which permits the patient to achieve reconstitution of a functioning hematopoietic system.
In many cases, successful mobilization is not effected in the patient and inadequate numbers of hematopoietic stem cells are harvested from these patients using current methods. Further, it is typically necessary to repeat the leukophoresis treatments, particularly if they are unsuccessful. This can be extremely stressful for the patient and the amount of stress increases with the number of repetitions.
Like normal HSCs, their malignant counterpart, leukemia initiating cells (LICs) reside in their BM niches that provide the structural and physiological conditions supporting their survival and growth. LICs are resistant to traditional chemotherapy by interacting with their BM microenvironment, which are the culprits of leukemia relapses after a period of remission induced by chemotherapy. In such instances, detachment of LICs from their niche by would be a valuable supplementary therapy to the traditional cancer therapies.